Process for racemizing an optically active N-benzylidene amino-acid amide

ABSTRACT

The invention relates to a process for racemizing an optically active N-benzylidene amino-acid amide, characterized in that a solution of the N-benzylidene amino-acid amide is mixed in a water-miscible organic solvent with at least 0.05 mole strong base per liter solution. 
     The invention further relates to a process for preparing an L-amino acid by enzymatic separation of the corresponding DL-amino-acid amide with an enzyme preparation from Pseudomonas putida, in which process also unconverted D-amino-acid amide is left behind in solution, characterized in that benzaldehyde is added to the solution, during which addition a precipitate of D-N-benzylidene amino-acid amide is being formed, this precipitate is subsequently, after being separated off, dissolved in an acetone-water mixture, 0.08-0.15 mole KOH/liter solution is subsequently added, the resulting solution is stirred for 1-20 hours at 20°-60° C., sulphuric acid is then added until the pH of the solution is 5 and the resulting sulphuric acid salt of the DL-amino-acid amide is finally, after isolation at pH 8-10, converted into the DL-amino-acid amide and this DL-amino-acid amide is used again.

The invention relates to a process for racemizing and optically active N-benzylidene amino-acid amide. Such a process is not known. The invention also relates to a process for racemizing an optically active amino-acid amide.

For a correct insight into the process according to the invention a number of definitions will now be given first. An optically active amino acid, optically active amino-acid amide, optically active N-benzylidene amino-acid amide and optically active Schiff base of an amino-acid amide are in this connection understood to mean an amino acid, amino-acid amide, N-benzylidene amino-acid amide respectively Schiff base of an amino-acid amide with an asymmetric carbon atom at the α-position and in which there is an excess of one of the optical antipodes in respect of the other. When here and hereinafter the term Schiff base of an amino-acid amide is used, it is meant to denote the same compound as N-benzylidene amino-acid amide.

There is a strong need of a process as described in the opening lines. The fact is that from U.S.-A-3971700 and U.S.-A-4080259 it is known how to prepare L-phenylglycine from DL-phenylglycine amide by means of selective enzymatic hydrolysis. However, in that process unconverted D-phenylglycine amide will remain in the hydrolysate also.

It is an economic necessity to have a process by which the undesired optical antipode of an amino-acid amide (in the case described above D-phenylglycine amide) can be racemized in order thus to make it possible for half of the starting material for the enzymatic hydrolysis to be recovered.

Applicant has now found that this racemization can be effected very advantageously through the formation of a Schiff base. For a major advantage is that then, according to, for instance, the process of U.S.-A-4172846, the said L-phenylglycine and D-phenylglycine amide can first be separated, without racemization, by means of the formation of a Schiff base and the same Schiff base of D-phenylglycine amide can then be racemized.

According to the invention an optically active N-benzylidene amino-acid is racemized is mixed by mixing a solution of the N-benzylidene amino-acid amide in a water-miscible organic solvent with at least 0.05 mole strong base per liter solution.

According to a particular mode of realizing the invention an optically active amino-acid amide is racemized by converting it into an optically active N-benzylidene amino-acid amide and racemizing the latter as mentioned above and converting the resulting racemic mixture into the DL-amino-acid amide.

Preference is given to preparing a DL-amino-acid amide from an optically active amino-acid amide by converting the optically active amino-acid amide into the corresponding optically active N-benzylidene amino-acid amide, mixing a solution of the N-benzylidene amino-acid amide in a water-miscible organic solvent with at least 0.05 mole strong base per liter solution, subsequently bringing this solution to pH 3-7 by the addition of acid and finally converting the resulting salt of the DL-amino-acid amide in an aqueous environment at pH 8-10 into the DL-amino-acid amide. Thus racemization of optically active N-benzylidene amino-acid amides and their subsequent conversion into the corresponding DL-amino-acid amides can be achieved very elegantly under relatively mild reaction conditions.

The process according to the invention can in principle be applied with all optically active N-benzylidene amino-acid amides.

Generally an optically active N-benzylidene amino-acid amide is prepared by converting benzaldehyde with an optically active amino-acid amide. The preparation of such compounds can be effected as described in U.S.-A-4172846. According to U.S.-A-4172846 the benzaldehyde may be substituted with, for instance, a hydroxyl group, nitro group, halogen, alkyl group with 1-6 C atoms, alkoxy group with 1-6 C atoms and a hydroxyalkyl group with 1-6 C atoms. It is stated in U.S.-A-4172846 that in principle aldehydes and ketones other than benzaldehyde can also be used as imine-forming agents, but that preference is given to benzaldehyde. Therefore, whenever here and hereinafter the term N-benzylidene is used, it is understood also to include substituted N-benzylidene compounds, the substituents of which may be the same as described in U.S.-A-4172846. However, other substituents can be used also. A wide variation in amino-acid amides, however, is also possible. Thus, for instance, the N-benzylidene derivatives of optically active phenylalanine, 3,4-dihydroxyphenylalanine, homophenylalanine, tyrosine, histidine, methionine, valine, leucine, alanine, phenylglycine, 4-hydroxyphenylglycine, 4-alkoxyphenylglycine and other substituted phenylglycines can be used.

The manner in which the optically Schiff base of the amino-acid amide was formed is not important for the process according to the invention. In addition to the said enzymatic separation of DL-amino-acid amides it is known from, for instance, U.S.-A-4036852 how to separate DL-phenylglycine amide into optical antiopodes via diastereoisomeric salt formation with an optically active 2-pyrrolidone-5-carboxylic acid. Also the undesired antipode obtained in this manner can be racemized with the process according to the invention. Neither is it important whether that Schiff base has the L-form or the D-form.

In a first step of the process according to the invention the optically active Schiff base of the amino-acid amide is dissolved in a water-miscible organic solvent, for instance acetone, methanol or ethanol.

At the same time or later at least 0.05 mole strong base per liter solution is added also, preferably 0.08-1.0 mole/liter, and subsequently the solution is stirred, for instance for 10 minutes to 24 hours. The strong base applied may be, for instance, NaOH, KOH, LiOH, Ca(OH)₂ or tetraalkylammonium hydroxide, in which each of the alkyl groups may contain 1-4 C atoms independently of any of the others. Also the said tetraalkylammonium hydroxide can be used in the form of a strongly basic ion exchanger with free OH groups.

The treatment with base may vary in time, for instance from 10 minutes to 24 hours. Often 15-100 minutes will suffice for racemization of the Schiff base to take place.

The temperature at which the racemization takes place is generally 20°-60° C. If a higher temperature is applied, some byproduct may be formed by hydrolysis and by the formation of diketopiperazine.

In a following step, if further processing to the DL-amino-acid amide is desired, a quantity of acid is added. The addition of acid on the one side serves to neutralize the strong base added and on the other to hydrolyze the Schiff base to form the corresponding salt of the amino-acid amide and the aromatic aldehyde. The acid applied may conveniently be hydrochloric acid or sulfuric acid. By the addition of acid the pH is brought to 3-7, preferably to about 5. The amount of acid is generally equivalent to the total amount of base in the solution, i.e. the amount of Schiff base plus the amount of strong base added.

The temperature in this step is preferably the same as in the preceding step, 20°-60° C. If the temperature rises too high, for instance to 100° C., and if the solution is strongly acid, the benzaldehyde compound may be split off and also an undesired saponification of the amide group may take place.

In this step the salt of the DL-amino-acid amide formed precipitates from the solution. This salt is subsequently separated off in the manner known in the art, for instance by filtration.

Finally, the salt is dissolved in water and, using base, the pH is brought to 8-10. The resulting solution is suitable for use in an enzymatic separation of the DL-amino-acid amide.

If an enzymatic separation of DL-amino-acid amides with an enzyme preparation from Pseudomonas putida is applied after racemization, preference is given to the use of KOH as base and sulfuric acid as acid, because the enzymatic activity of this preparation is stimulated by potassium ions and by sulfate ions.

In a special mode of realization, the process according to the invention is integrated into the preparation of an L-amino acid starting from the corresponding DL-amino-acid amide. Using an enzyme preparation from Pseudomonas putida an aqueous solution of the DL-amino-acid amide is subjected at 20°-60° C. and pH 8-10 to stereospecific hydrolysis to form the L-amino acid, ammonia and the D-amino-acid amide. To this solution, which contains the L-amino acid, ammonia and the D-amino-acid amide, benzaldehyde is added, during which addition a precipitate is formed of the D-N-benzylidene amino-acid amide. After being separated off by filtration or extraction this Schiff base is dissolved in an acetone-water mixture, upon which 0.08-1.0 mole KOH/l solution is added. The solution is now stirred for 1-20 hours at 20°-60° C. After addition of a quantity of H₂ SO₄ until a pH of 5 has been reached, a precipitate of the sulfuric acid salt of the DL-amino-acid amide is formed. After this salt is separated off and dissolved in water, the DL-amino-acid amide, which can again be used in the enzymatic hydrolysis, is formed at pH 8-10.

The racemization of an optically active N-benzylidene amino-acid amide can be incorporated also into a process for preparing DL-amino-acid amides from the corresponding DL-aminonitriles, (water-miscible) ketone and strong base (pH 11-14). Such a process is described in GB-A-1548032. Indeed, the reaction conditions described therein to prepare from the DL-aminonitrile the corresponding DL-amino-acid amide are about the same as those at which according to the present invention racemization of the Schiff base takes place. The undesired optical antipode of the amino-acid amide can therefore be converted advantageously into the Schiff base, and the latter can be returned to the step in wich the DL-aminonitrile is converted into DL-amino-acid amide. In this step racemization of the optically active N-benzylidene-amino-acid amide takes place. A treatment with strong acid, for instance sulfuric acid, then results in the formation of the (sulfuric acid) salt of the DL-amino-acid amide from DL-amino-acid amide (formed from the DL-aminonitrile), as well as from DL-N-benzylidene amino-acid amide (formed according to the mode of realizing the invention described herein). Treatment with KOH at pH 8-10 then yields the DL-amino-acid amide.

The invention is further elucidated hereinafter by means of the following examples.

Preparation of an optically active N-benzylidene amino-acid amide

By way of example a description is given below of the preparation of D-N-benzylidene valine amide. Similarly other starting compounds, to be used in the process according to the invention, can be prepared also.

In a 1-liter reaction flask provided with stirrer, thermometer, cooler, dropping funnel and heating jacket 66 g ammonium sulfate (0.5 mole) was dissolved at room temperature in 150 ml water and during stirring 250 ml ammonia (25% wt) was added. Subsequently, 65 g potassium cyanide (1.0 mole) and 110 ml water were added. Via the dropping funnel 95 ml isobutyraldehyde (1.0 mole) was subsequently slowly added in drops while ammonia gas was being introduced, at which the temperature did not rise beyond 40° C.

In order to allow this Strecker reaction to proceed in full the reaction mixture was stirred for 2.5 hours at the temperature obtained. The yield of DL-α-valinonitrile calculated on isobutyraldehyde was 93% according to HPLC analysis.

Subsequently, to this reaction mixture a mixture of 75 ml acetone and 100 ml water was added and the pH was set at 13.3. using 10 ml 8 molar potassium hydroxide solution. The temperature then rose from 33° C. to 41° C. in 0.5 hour.

This temperature was maintained for 6 hours, upon which 3.0 ml concentrated sulfuric acid was added to neutralize the potassium solution. Then distillation took place. In 1 hour 110 ml of a water-ammonia-acetone mixture was distilled over the top, while the bottom temperature rose to 102° C.

By means of HPLC analysis the yield of DL-α-valine amide was determined. This amounted to 88.4% calculated on the basis of isobutyraldehyde. The pH of the solution was 9.5. After removal of the potassium sulfate by filtration the solution was brought to 40° C. and 15 g of a preparation containing α-amino acyl amidase, obtained from a strain of Pseudomonas putida ATCC 12633, was subsequently added to it. After that the solution was stirred for 20 hours at 40° C.

Subsequently 45 ml benzaldehyde was slowly added to the solution in drops and stirring was continued for 0.5 hours more at 40° C.

The precipitated D-N-benzylidene valine amide was filtered off, washed on the filter with 4×75 ml water and dried for 16 hours at 45° C. and at 16 mbar. (From the filtrate L-valine can be recovered).

The yield of dry and (determined by means of thin-layer chromatography) pure D-N-benzylidene valine amide amounted to 82.6 g. The efficiency calculated on the basis of isobutyraldehyde was 40.5% and on the basis of valine amide 91.6%.

From the specific rotation [α]_(D) ²⁰ =-12.7 (CH₃ OH; C=2.0) a selectivity of 99.6% could be calculated. These two parameters are defined in example I.

Example I

Optically active N-benzylidene amino-acid amide was dissolved in the amount of acetone-water mixture stated in table 1 and the resulting solution was subsequently, after the addition of base, stirred for the time stated. Subsequently, while the stirring was continued, an amount of acid (H₂ SO₄ or HCl) was added in drops until a pH of 5 was obtained. After cooling to room temperature the salt of the DL-amino-acid amide formed was isolated by filtration over a glass filter. Subsequent washing took place with acetone (about 3 times the amount by weight of the DL-amino-acid amide salt formed). The yield and the degree of racemization of the tlc-pure (thin-layer chromatography) amino-acid amide salts are also mentioned in table 1. The yield has been calculated as a percentage of the starting quantity in moles. ##EQU1## where 1 is the length of the polarimeter tube in dm and c the number of grammes of product per 100 ml volume.

The selectivity is expressed as follows: ##EQU2## In case of pure DL-amino-acid amide the selectivity is 50%.

The maximum [α]_(D) ²⁰ of a number of salts of optically active amino-acid amides is mentioned in Greenstein & Winitz, vol. 2, pages 1196-1200, as well as in Beilstein 14 III, page 1489. The following maximum [α]_(D) ²⁰ values the following amino-acid amide salts were found by own observation:

    ______________________________________                                         D-methionine amide.HCl                                                                             -18.2° (C = 1.0, H.sub.2 O)                         D-homophenylalanine amide.sulfate                                                                  -15.7° (C = 1.0, H.sub.2 O)                         L-phenylalanine amide.sulfate                                                                      +17.8° (C = 1.0, H.sub.2 O)                         ______________________________________                                    

                                      TABLE 1                                      __________________________________________________________________________     Racemization and isolation of amino-acid amide salts                                                   dura-                                                                          tion                                                                               yield spec. rota-                                                                          selec-                                 N--benzylidene     tempera-                                                                            in  amide.                                                                               tion [α].sub.D .sup.20                                                         tivity                                 compound                                                                               solvent                                                                               base                                                                               ture °C.                                                                     hours                                                                              salt  in °                                                                          in %                                   __________________________________________________________________________     100 mmoles                                                                             285 ml 3 ml                                                                               60   19  90,5% -0,8  51,4                                   D-valine                                                                               acetone +                                                                             8 N          HCl--salt                                          amide   15 ml water                                                                           KOH                                                             10 mmoles                                                                              19 ml ace-                                                                            0,2 ml                                                                             25   24  84,1% -0,2  50,9                                   D-leucine                                                                              tone 1 + 1 ml                                                                         8 N          HCl--salt                                          amide   water  KOH                                                             1000 mmoles                                                                            1425 ml                                                                               15 ml                                                                              45   2   98,6% -0,3  51,0                                   D-homophe-                                                                             acetone +                                                                             8 N          sulfate                                            nylalanine                                                                             75 ml water                                                                           KOH                                                             amide                                                                          20 mmoles                                                                              38 ml ace-                                                                            0,4 ml                                                                             25   3   86,7% -0,1  50,3                                   D-methionine                                                                           tone + 2                                                                              8 N          HCl--salt                                          amide   ml water                                                                              KOH                                                             50 mmoles                                                                              95 ml ace-                                                                            1,0 ml                                                                             20   2   96,5%  0,0  50,0                                   D-phenylgly-                                                                           tone + 5                                                                              8 N          HCl--salt                                          cine amide                                                                             ml water                                                                              KOH                                                             100 mmoles                                                                             190 ml 1,0 ml                                                                             25   2   96,7%  0,0  50,0                                   L-phenyl-                                                                              acetone +                                                                             10 N         sulfate                                            alanine 10 ml water                                                                           NaOH                                                            amide                                                                          __________________________________________________________________________

EXAMPLE II

In the manner described in example I a number of optically active N-benzylidene amino-acid amides were racemized by incorporating these compounds in an organic solvent, mixed or not mixed with water, and subsequently treating them with an aqueous base solution. Table 2 shows the amounts, racemization conditions, optical rotations and selectivities for these Schiff bases. Unlike example I, no salts of the respective Schiff bases were isolated in example II, but the racemization rate of the Schiff bases itself was examined. After the duration given it was revealed by thin-layer chromatography that there had been no hydrolysis to amino acid and that, moreover, no other products such as, for instance, diketopiperazine had been formed.

                                      TABLE 2                                      __________________________________________________________________________                               dura-                                                                          tion     selec-                                      N--benzylidene      tempera-                                                                             in  α mea-                                                                        tivi-                                       compound                                                                               solvent                                                                              base  ture °C.                                                                      min.                                                                               sured in °                                                                   ty in %                                     __________________________________________________________________________     2.2 mmoles                                                                             10 ml 0.1 ml                                                                               25    0   -0.400                                                                              100.0                                       D-phenylgly-                                                                           CH.sub.3 OH                                                                          8 N         10  -0.004                                                                              50.5                                        cine amide    KOH         15  -0.002                                                                              50.2                                        2.2 mmoles                                                                             10 ml 0.1 ml                                                                               25    0   -10.500                                                                             100.0                                       L-phenylala-                                                                           CH.sub.3 OH                                                                          10 N        15  -4.250                                                                              70.2                                        nine amide    NaOH        25  -1.650                                                                              57.9                                                                  40  -0.160                                                                              50.8                                        1.2 mmoles                                                                             9 ml ace-                                                                            0.1 ml                                                                               25    0   +0.900                                                                              100.0                                       D-homophe-                                                                             tone + 2                                                                             8 N         20  +0.450                                                                              75.0                                        nylalanine                                                                             ml water                                                                             KOH         40  +0.190                                                                              60.6                                        amide                     80  +0.037                                                                              52.1                                        1.1 mmoles                                                                             8 ml ace-                                                                            0.1 ml                                                                               25    0   -8.10                                                                               100.0                                       L-trypto-                                                                              tone + 2                                                                             8 N         30  -2.16                                                                               63.3                                        phane amide                                                                            ml water                                                                             KOH         60  -0.44                                                                               52.7                                        1.4 mmoles                                                                             10 ml 0.1 ml                                                                               25    0   +1.77                                                                               100.0                                       D-methionine                                                                           CH.sub.3 OH                                                                          8 N         15  +0.36                                                                               60.2                                        amide         KOH         30  +0.05                                                                               51.4                                        2.2 mmoles                                                                             9 ml  1.0 ml                                                                               25    0   -5.270                                                                              100.0                                       L-histidine                                                                            CH.sub.3 OH                                                                          tetra-      2   -2.160                                                                              70.5                                        amide         methyl      6   -0.525                                                                              55.0                                                      ammo-       12  -0.150                                                                              51.4                                                      nium-                                                                          hydro-                                                                         xide                                                                           (10                                                                            gew. %)                                                          4.4 mmoles                                                                             20 ml 1 g.  25    0   -11.430                                                                             100.0                                       L-phenyl-                                                                              CH.sub.3 OH +                                                                        Dowex       30  -2.413                                                                              60.6                                        alanine 0,2 ml H.sub.2 O                                                                     I in        60  -0.524                                                                              52.3                                        amide         OH--form    75  -0.295                                                                              51.3                                        __________________________________________________________________________

COMPARATIVE EXAMPE 1

To 50 mmoles D-N-benzylidene homophenylalanine amide 50 ml water and 5 mmoles KOH were added. A suspension of the said optically active compound in water was formed. This suspension was stirred for 24 hours at 25° C. After filtration and drying it was found that there had been no racemization. Apparently the Schiff base must be soluble in order to be capable of being racemized.

COMPARATIVE EXAMPLES 2-3

In a flask 2.2 mmoles L-phenylglycine amide was dissolved in 10 ml methanol resp. 8 ml acetone with 2 ml water. In the manner described in example II base was added and the optical rotation was measured at intervals. The results are given in table 3. They show that without the form of a Schiff base there is no racemization of the optically active phenylglycine amide. They also show that, as a potential imine-forming agent, acetone does not induce racemization, or hardly so, in other words that acetone only serves as solvent.

                                      TABLE 3                                      __________________________________________________________________________                       temp.                                                                              duration                                                                            α measured                                                                     selectivity                                   Compound                                                                              solvent                                                                             base  °C.                                                                         in min.                                                                             in °                                                                          in %                                          __________________________________________________________________________     2.2 mmoles                                                                            10 ml                                                                               0.1 ml                                                                               25  0    +2.150                                                                               100                                           l-phenylgly-                                                                          CH.sub.3 OH                                                                         8 N KOH   10   +2.130                                                                               99.5                                          cine amide            70   +2.110                                                                               99.1                                          2.2 mmoles                                                                            8 ml 0.1 ml                                                                               25  0    +2.180                                                                               100                                           L-phenylgly-                                                                          acetone                                                                             8 N KOH   10   +2.140                                                                               99.5                                          cine amide                                                                            2 ml H.sub.2 O 60   +1.930                                                                               94.3                                          __________________________________________________________________________

COMPARATIVE EXAMPLE 4

Of a solution of 2.2 mmoles D-N-benyzlidene phenylglycine amide in 10 ml methanol the optical rotation was determined, without the addition of base, after 0 minute, 10 minutes and 30 minutes. It was found to be -0.401°, -0.400° and -0.410° respectively. Consequently, there had been no racemization. This experiment shows that addition of base is essential for racemization.

COMPARATIVE EXAMPLES 5-6

In the manner described in comparative example 4 the racemization of D-N-benzylidene-phenylalanine amide was carried out in the presence of the weak bases of ammonia resp. triethylamine. Table 4 shows that these bases are not strong enough to effect the racemization.

                                      TABLE 4                                      __________________________________________________________________________                               dura-                                                                          tion                                                                               α mea-                                                                        selec-                                      N--benzylidene      tempera-                                                                             in  sured                                                                               tivity                                      compound                                                                               solvent                                                                              base  ture °C.                                                                      min.                                                                               in °                                                                         in %                                        __________________________________________________________________________     2,2 mmoles                                                                             10 ml 0.1 ml                                                                               25    0   -10.338                                                                             100.0                                       L-phenylala-                                                                           CH.sub.3 OH                                                                          con-        60  -9.543                                                                              96.2                                        nine amide    cen-        180 -9.043                                                                              93.7                                                      trated                                                                         ammo-                                                                          nia                                                              2.2 mmoles                                                                             10 ml 0.14  25    0   -10.415                                                                             100.0                                       L-phenylala-                                                                           CH.sub.3 OH                                                                          ml          60  -10.273                                                                             99.3                                        nine amide    tri-        180 -9.933                                                                              97.7                                                      ethyl-                                                                         amine                                                            __________________________________________________________________________

COMPARATIVE EXAMPLE 7

A solution of 4.0 g D-N-benzylidene-phenylglycine amide in 400 ml toluene was boiled (112° C., atmospheric pressure) for 20 hours while being stirred continuously. At the times stated a sample was taken to determine the rotation. These measured α-values are shown in table 5. They show that no thermal racemization took place.

                  TABLE 5                                                          ______________________________________                                         time in hours                                                                               α measured in °                                                               selectivity in%                                       ______________________________________                                         0            -0.044      100                                                   2            -0.045      100                                                   4            -0.044      100                                                   20           -0.044      100                                                   ______________________________________                                     

We claim:
 1. Process for racemizing an optically active N-benzylidene amino-acid amide, wherein a solution of the N-benzylidene amino-acid amide in a water-miscible organic solvent is mixed with at least 0.05 mole strong base per liter solution.
 2. Process for preparing a DL-amino-acid amide from an optically active amino-acid amide, wherein an optically active amino-acid amide is converted into the corresponding N-benzylidene amino-acid amide, a solution of the N-benzylidene amino-acid amide in a water-miscible organic solvent is subsequently mixed with at least 0.05 mole strong base per liter solution and the resulting DL-N-benzylidene amino-acid amide is converted into the DL-amino-acid amide.
 3. Process according to claim 2, wherein the DL-N-benzylidene amino-acid amide is converted into the DL-amino-acid amide by bringing the solution containing DL-N-benzylidene amino-acid amide with acid to pH 3-7 and by subsequently converting the formed DL-amino-acid amide salt in an aqueous medium at pH 8-10 into the DL-amino-acid amide.
 4. Process according to claim 1, wherein the racemization is carried out with 0.08-1.0 mole strong base per liter solution.
 5. Process according to claim 1, wherein the strong base used is NaOH, KOH, LiOH, Ca(OH)₂ or tetraalkylammonium hydroxide, in which each of the alkyl groups contains 1-4 C atoms independently of any of the others.
 6. Process according to claim 5, wherein tetraalkylammonium hydroxide is used in the form of a basic ion exchanger with free OH⁻⁻ groups.
 7. Process according to claim 1, wherein the organic solvent applied is acetone, methanol or ethanol.
 8. Process according to claim 3, wherein the acid used is hydrochloric acid or sulfuric acid.
 9. Process according to claim 3, wherein the acid is used in an amount equivalent to the total amount of base (Schiff base+strong base).
 10. Process according to claim 3, wherein the DL-amino-acid amide is obtained from the corresponding salt while using KOH.
 11. Process according to claim 1, wherein after addition of strong base the solution is stirred for 10 minutes to 24 hours. 